The overall objective of this program is ultimately to provide better chemotherapyy for human cancer. To accomplish that objective, a coordinated series of multidisciplinary studies will be conducted as follows: 1) Selected compounds synthesized within our Institute and materials from outside will be tested in established experimental tumor systems and several special models for antitumor activity and in other systems for antiherpes virus activity. (Synthesis projects: 1,3,4; antitumor testing projects: 9, 10, 11, 12, 13, 14; antivirus testing: 1). 2) Additional systems, new or new in our laboratory, will be developed and utilized for antitumor tests, such as a rat colon carcinoma, human cancers in nude mice, neurological tumor models and tumors from macrophages, T and B cells. (New antitumor test systems projects: 12, 13, 14). 3) The usefulness of available chemotherapeutic agents will be improved by the development of new combination therapy regimens, including added immunopotentiation. (Projects: 9, 10, 11, 12, 13, 14). 4) Mechanisms of action studies will be conducted on active compounds and in resistant tumor or leukemia lines. Also basic studies with multiple approaches to improve anti-fol therapy. (Mechanism of action and resistance studies: 1, 4, 6, 8, 9, 10, 16, 17; improvement of anti-fol therapy: 9, 16).